Sulfate conjugation (sulfonation) is an important pathway in the biotransformation of steroid hormones. These reactions are catalyzed by a superfamily of cytosolic sulfotransferase (SULT) enzymes. In humans, the SULT2B1 gene encodes two isoforms, SULT2B1a and SULT2B1b, that catalyze the sulfonation of steroid hormones including dehydroepiepiandrosterone and dihydrotestosterone. SULT2B1 is expressed in steroid hormone-responsive tissues including prostate and breast. The goal of this research proposal seeks to elucidate a novel regulatory pathway, catalyzed by SULT2B1, that abrogates steroid- hormone dependent cellular processes. The proposed studies will evaluate the proliferative and transcriptional responses of cells expressing SULT2B1 and naturally occurring polymorphic SULT2B1 alloenzymes toward androgens. In complementary work, the functional significance of an evolutionarily acquired, novel proline-rich domain in SULT2B1 will be evaluated for its contribution to protein-protein interactions. Finally, the functional significance of common genetic SULT2B1 polymorphisms will be evaluated. Together these studies have the potential to elucidate a novel regulatory pathway, catalyzed by SULT2B1, that abrogates steroid hormone-dependent cellular processes in humans.